Renal histology of Fanconi syndrome associated with adefovir dipivoxil: A case report.

A sporadic occurrence of Fanconi syndrome associated with adefovir dipivoxil (ADV) has been reported, particularly when confirmed by renal biopsy. This study presents the case of a 53-year-old man who had been taking ADV 10 mg daily for 10 years to treat chronic hepatitis B (CHB) and subsequently developed Fanconi syndrome. The clinical manifestations included hypophosphatemic osteomalacia, glucosuria, renal tubular acidosis, low-molecular-weight proteinuria, and renal insufficiency. Renal biopsy revealed significant injury to proximal tubular epithelial cells, including vacuolar degeneration and regeneration of tubular epithelial cells. The ultrastructural pathology indicated severe morphological abnormalities of mitochondria, such as densely packed and enlarged mitochondria, with loss, blunting, and disordered arrangement of cristae. Following discontinuation of ADV and supplementation with oral phosphate, hypophosphatemia, glucosuria, and proteinuria were resolved. These findings support the previous hypothesis that ADV-induced nephrotoxicity may involve mitochondrial injury.

Fanconi syndrome, diabetes insipidus, and acute kidney injury due to tenofovir disoproxil fumarate: A case report.

BACKGROUND: Tenofovir disoproxil fumarate is widely used in Botswana as part of the first-line antiretroviral regimen in the 'Treat All' strategy implemented in 2016 by the Ministry of Health. Its use has been associated with several uncommon adverse renal effects, though rarely all in conjunction or without the combined use of protease inhibitors. CASE PRESENTATION: A 49-year-old woman living with HIV whose viral load is suppressed on tenofovir disoproxil fumarate, lamivudine, and dolutegravir presented with 1 day of generalized weakness and myalgia causing an inability to ambulate. This was associated with nausea and vomiting and profound fatigue. She was found to have an acute kidney injury, non-anion-gap metabolic acidosis, hypernatremia, hypokalemia, and hypophosphatemia. Urinalysis revealed pyuria with white blood cell casts, glucosuria, and proteinuria. The diagnosis was made of tenofovir-induced nephrotoxicity. The tenofovir was discontinued, and the patient was initiated on intravenous fluids and electrolyte and bicarbonate supplementation with improvement in her symptoms and laboratory values. CONCLUSIONS: This report suggests the possibility of severe tenofovir-induced nephrotoxicity with combined acute kidney injury, Fanconi syndrome, and nephrogenic diabetes insipidus in the absence of other provoking factors such as use with protease inhibitors or advanced HIV disease, chronic kidney disease, and age. With its wide use in Botswana and other countries, health-care providers should have a high index of suspicion for tenofovir-induced nephrotoxicity for HIV patients on tenofovir with deranged renal function tests and electrolytes.

Fanconi Syndrome Associated with Long-term Treatment with Zoledronate.

Intravenous bisphosphonate therapy is used to prevent fractures in the management of bone metastasis. However, it may induce renal damage. We herein report an 81-year-old woman with Fanconi syndrome and osteomalacia who had been diagnosed with metastatic breast cancer and received treatment with zolendronate for over 5 years. Her bone markers normalized after switching zolendronate to denosmab and starting vitamin D and mineral supplementation. This case shows that chronic renal damage induced by zolendronate can cause osteomalacia. In patients with intravenous zolendronate therapy, close monitoring of renal and bone markers is needed, even under long-term therapy.

Description of a transient proximal tubulopathy induced by amino acids perfusion in peptide receptor radionuclide therapy: A case report.

RATIONALE: Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs is a targeted internal radiotherapy method used to treat tumors expressing somatostatin receptors. Concomitant amino acids perfusion is systematically performed in order to inhibit the proximal tubular uptake of the radionuclide and thus prevent nephrotoxicity. PATIENT CONCERNS:: a 67-year-old woman with an intestinal neuroendocrine tumor with multiple lymphadenopathies and liver metastases. The patient displayed a carcinoid syndrome with flushes including facial erythrosis and paresthesia. During the treatment, the patient exhibited emesis and severe cramps. DIAGNOSIS: We describe incomplete proximal tubulopathy induced by an amino acid therapy with [177Lu]-DOTA0-Tyr3-octreotate, which was reversible after treatment discontinuation. This diagnosis relies on metabolic acidosis, hypophosphatemia due to renal loss, tubular proteinuria and generalized aminoaciduria. Serum creatinine remained stable during and after the procedure. INTERVENTIONS: PRRT with radiolabeled somatostatin analog ([177Lu]-DOTA0-Tyr3-octreotate). In order to prevent PRRT induced nephrotoxicity, we used a solution of 20 amino acids including 22 g/L Lysine and 16.8 g/L Arginine. Metoclopramide was successfully used to control vomiting. During the treatment and at the time of cramps, the blood sample showed hypophosphatemia at 0.3 mmol/L justifying intravenous phosphate supplementation. The cramps disappeared after this infusion. OUTCOMES: Hypophosphatemia with low TmPO4/GFR was observed as well as an increase in ß2-microglobulinuria, urinary polyclonal light chains, and amino aciduria involving all amino acids. All these disturbances disappeared the day after the treatment and there was no acute kidney injury after 5 PRRT sessions. Six months after PRRT discontinuation, the patient had neither renal failure nor proximal tubulopathy. Aminoacid induced tubulopathy involves the main ligands of the megalin receptor. It has recently been demonstrated that cilastatin is a megalin inhibitor in the proximal tubule and therefore could represent an attractive alternative to amino acids for this purpose. LESSONS: This case report is a description of a nephroprotective strategy in which partial, and transient tubulopathy is induced, in order to decrease proximal absorption of a tubulotoxic molecule. This little known strategy could be used to prevent proximal tubular injury caused by others megalin-mediated nephrotoxicity medication.

Denosumab improves clinical manifestations of hypophosphatemic osteomalacia by adefovir-induced Fanconi syndrome: a case report.

BACKGROUND: Adefovir dipivoxil is a nucleotide analogue that is approved for treatment of chronic hepatitis B. Adefovir dipivoxil is associated with proximal tubular dysfunction, resulting in Fanconi syndrome, which can cause secondary hypophosphatemic osteomalacia. We describe a case of a patient with hypophosphatemic osteomalacia secondary to Fanconi syndrome induced by adefovir dipivoxil concomitantly with osteoporosis in whom clinical symptoms were improved by adding denosumab (a human monoclonal antibody targeting the receptor activator of nuclear factor-κB ligand) to preceding administration of vitamin D3. CASE PRESENTATION: A 60-year-old Japanese man had been receiving low-dose adefovir dipivoxil (10 mg/day) to treat chronic hepatitis B for approximately 5 years. He presented to an orthopedic surgeon with severe pain of the right hip and no trauma history, and fracture of the neck of the right femur was identified. In addition, 99mTc-hydroxymethylene diphosphate scintigraphy revealed significantly abnormal uptake in the bilateral ribs, hips, and knees, and he was therefore referred to our university hospital for evaluation of multiple pathological fractures. We diagnosed hypophosphatemic osteomalacia due to Fanconi syndrome induced by adefovir dipivoxil therapy. Although we reduced the patient's adefovir dipivoxil dose and added calcitriol (active vitamin D3), he did not respond and continued to complain of bone pain. Several bone resorption markers and bone-specific alkaline phosphatase were also persistently elevated. Therefore, we added denosumab to vitamin D3 supplementation for treatment of excessive bone resorption. Two months after initiation of denosumab, his hip and knee pain was relieved, along with a decrease in serum alkaline phosphatase and some bone resorption markers. CONCLUSIONS: Although denosumab is not generally an appropriate treatment for acquired Fanconi syndrome, it may be useful for patients who have hypophosphatemic osteomalacia due to adefovir dipivoxil-induced Fanconi syndrome associated with excessive bone resorption. However, clinicians should keep in mind that if denosumab is administered to patients with hypophosphatemic osteomalacia accompanied by excessive bone resorption, adequate vitamin D and/or phosphate supplementation should be done before administration of denosumab.

Kidney Biopsy Findings in a Patient With Valproic Acid-Associated Fanconi Syndrome.

A 7-year-old boy with a history of febrile illness-related epilepsy syndrome presented with proteinuria and elevated creatinine. His severe epileptic disorder has been treated since age 2 with multiple antiepileptic medications, including valproic acid. More recently, he was noted to have features of Fanconi syndrome with acidosis, hypophosphatemia, hypokalemia, glucosuria, and nephrotic-range proteinuria. This was managed with supplements; however, in the setting of rising creatinine and prominent proteinuria, a kidney biopsy was performed. Renal cortex revealed markedly decreased expression of proximal tubule markers and increased expression of markers of distal nephron differentiation. Such findings have been described in several genetic and acquired conditions, including renal tubular dysgenesis, severe hypoxic injury following renal artery stenosis, and toxic injury related to in utero exposure to angiotensin-converting-enzyme inhibitors. Such changes have not been reported before in valproic acid-associated Fanconi syndrome, although in general, morphologic findings in this condition have not been well established in the literature.

Pathologic Femoral Neck Fracture Due to Fanconi Syndrome Induced by Adefovir Dipivoxil Therapy for Hepatitis B.

In Fanconi syndrome, hypophosphatemic osteomalacia is caused by proximal renal tubule dysfunction which leads to impaired reabsorption of amino acids, glucose, urate, and phosphate. We present a rare case of a 43-year-old Korean male who was found to have insufficiency stress fracture of the femoral neck secondary to osteomalacia due to Fanconi syndrome. He had been receiving low-dose adefovir dipivoxil (ADV, 10 mg/day) for the treatment of chronic hepatitis B virus infection for 7 years and he subsequently developed severe hypophosphatemia and proximal renal tubule dysfunction. The incomplete femoral neck fracture was fixed with multiple cannulated screws to prevent further displacement of the initial fracture. After cessation of ADV and correction of hypophosphatemia with oral phosphorus supplementation, the patient's clinical symptoms, such as bone pain, muscle weakness, and laboratory findings improved.

Outcome of renal proximal tubular dysfunction with Fanconi syndrome caused by sodium valproate.

BACKGROUND: Although Fanconi syndrome is rare in patients with epilepsy treated with sodium valproate (VPA), the prevalence might be higher in children with severe motor and intellectual disabilities (SMID). VPA-induced Fanconi syndrome usually has a favorable outcome, but the long-term outcome of renal tubular dysfunction in SMID patients remains unknown. The aim of this study was therefore to investigate the long-term outcome of renal proximal dysfunction in SMID children with Fanconi syndrome caused by VPA. METHODS: The records of six children with SMID and Fanconi syndrome caused by VPA were retrospectively reviewed to assess long-term proximal renal tubular function after discontinuation of VPA. All six patients had intractable epilepsy and required tube feeding. RESULTS: Proximal tubular dysfunction improved in almost all patients after VPA discontinuation, although abnormal uric acid reabsorption persisted in three patients. Five patients had hypocarnitinemia. After carnitine supplementation, one of these three patients with decreased ability to reabsorb uric acid had a normal serum level and improved fractional excretion of uric acid. CONCLUSIONS: Secondary carnitine deficiency may cause prolonged tubular dysfunction in some SMID patients with VPA-induced Fanconi syndrome. Fanconi syndrome caused by VPA is a usually reversible dysfunction of the proximal tubules, but can be permanent. Although not effective for all patients, carnitine is recommended for patients with VPA-induced Fanconi syndrome, especially children with SMID.

Sodium valproate-induced Fanconi type proximal renal tubular acidosis.

We present a case series of three patients with sodium valproate-induced Fanconi's syndrome, with ages ranging from 5 years to 12 years. The most important diagnostic features of this syndrome include hypophosphataemia, glycosuria and proteinuria, which are also noted in our series. Furthermore, also added is that clinical fractures representing an underlying osteopaenia may provide an opportunity for early intervention as it raises the suspicion of Fanconi's syndrome. Previous case reports suggest there is a subpopulation of individuals who are at risk of developing this condition. These individuals share similar characteristics, including being non-ambulatory, developmentally delayed and/or tube fed. Withdrawing sodium valproate therapy is the ultimate treatment for valproate-induced Fanconi's syndrome and from previous case series, normalised renal function occurs in approximately 6 months. Often, supplement support is also required for deranged electrolyte balance.

Fanconi syndrome caused by low-dose adefovir dipivoxil.

Adefovir dipivoxil (ADV) at a low-dose (10 mg daily), which was previously considered not nephrotoxic, was reported to have induced acquired Fanconi syndrome (FS). We report one 64-year-old Chinese woman and 2 Chinese men (ages 45 and 63 years) with bone pain, and/or muscle weakness on ADV therapy were diagnosed with low-dose ADV-induced FS. The serum phosphate normalized, or nearly normalized in the first and second patients after changing ADV to entecavir with, or without phosphate supplement, but did not improve significantly in the third patient after changing ADV to tenofovir, even though he was supplied with a higher dose of phosphate. Low-dose ADV-related FS is not rare in the Asian population. Regular monitoring of urine and serum phosphate is necessary during therapy with ADV. Prognosis was favorable, however, tenofovir is not a suitable replacement for ADV.

A case report of deferasirox-induced kidney injury and Fanconi syndrome.

Cases of kidney injury associated with the use of deferasirox chelation therapy during the course of treatment for iron overload have been reported infrequently. We present the case of a patient treated with deferasirox who had biopsy-proven tubular injury in the setting of clinical Fanconi syndrome. The patient required hospitalization for metabolic acidosis, electrolyte abnormalities, and associated symptoms. With supportive care and cessation of chelation therapy he improved, but has yet to fully recover. This is the first known case reporting biopsy-proven tubular damage in the setting of deferasirox use.

Clinical and pathological spectrums of aristolochic acid nephropathy.

AIM: To study the clinical and pathological characteristics of aristolochic acid nephropathy (AAN). METHODS: 86 patients with AAN during 2001 and 2009 in our department were recruited in this retrospective study. The clinical and pathological features were analyzed. RESULTS: There were 47 males and 39 females, aging from 12 to 69 years old. Abnormal urine analysis and gastro-intestinal diseases were two main underlying causes for patients taking aristolochic acid (AA) containing drugs. All patients suffered from renal function impairment. 19 patients (22.0%) presented with acute kidney injury (AKI), while 67 patients (78%) presented as chronic cases. Among them, 31 patients (36.0%) lacked symptoms, 30 patients (34.8%) were accompanied with hypertension, and 26 patients (30.2%) presented with gastrointestinal symptoms. Laboratory examination revealed elevated urine retinol-binding protein (RBP) (90.7%) and urine N-acetyl-ß-glucosaminidase (NAG) (80.2%). Anemia and glucosuria accounted for 64.0% and 58.1%, respectively. Renal biopsy showed prominent tubular brush border ablation (84.2%) in acute cases, while obvious tubular basement membrane (TBM) thickening (81.4%) and interstitial fibrosis were present in chronic cases. During the follow- up, 11 (57.9%) acute cases gained renal function recovery. They had lower urine RBP level and lower incidence of hypokalemia than the non-recovery acute cases. In the chronic group, 27 patients (40.2%) progressed to endstage renal disease (ESRD), with 11 dialysis and 5 renal transplantation cases. CONCLUSION: AAN patients usually suffered from renal impairment with an associated history of taking AA containing drugs. Proximal renal tubular dysfunction and structure destroying would be the main positive findings in laboratory tests and renal biopsy. Urine RBP and hypokalemia might determine the outcome of acute AAN patients.

Iron chelation treatment with deferasirox prior to high-dose chemotherapy and autologous stem cell transplantation may reduce the risk of hepatic veno-occlusive disease in children with high-risk solid tumors.

BACKGROUND: We evaluated whether iron chelation treatment during induction chemotherapy could safely reduce serum iron levels and thereby reduce the frequency of hepatic veno-occlusive disease (VOD) during high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT) in children with high-risk solid tumors. PROCEDURE: Children diagnosed with high-risk solid tumors between August 2008 and July 2009 were enrolled. Deferasirox treatment (25 mg/kg/day) was initiated when serum ferritin levels increased to more than 1,000 ng/ml during induction chemotherapy. Patients who were diagnosed with the same disease between April 2005 and June 2007 and treated in the same way without any iron chelation treatment formed the control group. Efficacy and toxicity of deferasirox treatment were compared between the two groups. RESULTS: Eighteen of 20 patients enrolled received deferasirox treatment. Deferasirox treatment was completed as scheduled in 11 (61.1%) of them without dose reduction or discontinuation. The serum ferritin levels prior to HDCT/autoSCT were lower in the deferasirox group than in the control group (median 1,268 ng/ml vs. 1,828 ng/ml, P < 0.001), although there was no difference in the RBC transfusion amount between the two groups. While 7 (17.9%) VODs developed during 39 HDCT/autoSCTs in the control group, there was no VOD during 40 HDCT/autoSCTs in the deferasirox group (P = 0.005). However, renal dysfunction (38.9%) including Fanconi syndrome (16.7%) was a frequently observed adverse effect of deferasirox treatment. CONCLUSIONS: Deferasirox treatment during induction chemotherapy reduces the frequency of VOD during HDCT/autoSCT. The development of renal dysfunction should be closely monitored during deferasirox treatment.

Fanconi syndrome in a patient with ß-thalassemia major after using deferasirox for 27 months.

BACKGROUND: Deferasirox (DFRA) is a new approved oral iron chelator. Its advantages are that it is convenient and better tolerated and adhered to due to "once-daily" oral dosage. However, its use in the field is limited and it is yet to be subjected to postmarketing surveillance. CASE REPORT: A 18.75-year-old male with ß-thalassemia major received oral DFRA therapy due to transfusional iron overload for 27 months. He had received iron chelation therapy with deferoxamine injection together with oral deferiprone. However, his compliance was poor (very high routine serum ferritin level, ranging from 1059 to 6030 ng/mL). After 25 months of DFRA therapy, the serum ferritin level declined from 4097 to 1343 ng/mL. He experienced five hospital admissions including coma, Fanconi syndrome, hepatic dysfunction, and thrombocytopenia after using DFRA as oral iron chelator. After we discontinued DFRA, he recovered fully without hepatic dysfunction, thrombocytopenia, proteinuria, glucosuria, and hypophosphatemia. CONCLUSIONS: Our case illustrates the potential risks of DFRA-induced renal toxicity, hepatic dysfunction, and thrombocytopenia. Meticulous monitoring of kidney, liver, and hematopoietic function is mandatory for patients undergoing treatment with DFRA. Further investigation of the potential risk and adverse effects of long-term DFRA use is necessary.

Hypophosphataemic osteomalacia in patients on adefovir dipivoxil.

Fanconi syndrome results from generalised renal tubular toxicity and, owing to phosphate wasting can cause hypophosphataemic osteomalacia. Large clinical trials advocated the safety of adefovir dipivoxil at a daily dose of 10 mg, the standard dose given to patients with hepatitis B. We diagnosed Fanconi syndrome in conjunction with severe osteomalacia in 2 hepatitis B-positive patients on standard-dose adefovir therapy. The first patient was a 40-year-old male with a 5 month history of bone pain involving his knees, ankles, and ribs. He had been receiving adefovir dipivoxil for 27 months before the development of hypophosphataemia, urinary phosphate wasting, and aminoaciduria. These abnormalities resolved within weeks of discontinuation of adefovir dipivoxil and supplementation with elemental phosphate, calcium carbonate, and cholecalciferol. The second patient was a 53-year-old female with a 6 month history of lethargy, cachexia, and generalized bone pain. She had been receiving adefovir for 64 months before the development of these symptoms. She had hypophosphataemia, hypocalcaemia, metabolic acidosis, and severe vitamin D deficiency, but initially no urinary phosphate wasting. Four months of high-dose cholecalciferol supplementation unmasked her Fanconi syndrome including significant urinary phosphate wasting. The patient improved within weeks of discontinuation of adefovir and supplementation with elemental phosphate, calcium carbonate, and calcitriol. Despite large clinical trials advocating the safety of adefovir dipivoxil at 10-mg daily, long-term use of this agent may be nephrotoxic and in rare cases, cause Fanconi syndrome and severe hypophosphataemic osteomalacia. Clinicians prescribing this drug should be aware of this potential complication.

Tenofovir-associated severe bone pain: I cannot walk!

Two adult patients living with AIDS presented with severe bone pain associated with tenofovir (TDF) use. Both were unable to walk without assistance and were severely restricted in their movement due to the bone pain. Both had mild renal impairment, Fanconi syndrome, and bone mineral density (BMD) loss. Bone pain and inability to walk were reversible with the cessation of TDF and supplementation with Vitamin D(3), calcium, and phosphate. These cases appear to be examples of the severity of BMD loss associated with TDF use and suggest not only attention to renal function with TDF use, but also monitoring of alkaline phosphatase (bone fraction) and plasma phosphorus as indicators of BMD loss.

Osteomalacia hipofosfatémica en un paciente infectado por VIH en tratamiento con Tenofovir / Hypophosphatemic osteomalacia in a patient HIV-positive treated with Tenofovir

En pacientes infectados por VIH en tratamiento con tenofovir se ha comunicado la ocurrencia de hipofosfatemia y osteomalacia. Presentamos un caso que debutó clínicamente con fracturas vertebrales y dolor óseo. La suspensión de la medicación y la corrección de la acidosis mejoraron la sintomatología. El caso ilustra la importancia de considerar la osteomalacia en pacientes tratados con tenofovir

Cases of hypophosphatamia and osteomalacia have been reported in HIVpositive patients on tenofovir-containing active antiretroviral therapy. We present a case in which vertebral fractures and bone pain were the presenting features. The symptoms resolved after discontinuation of tenofovir and with mineral supplementation. The case highlights the importance of considering the diagnosis of osteomalacia in patients treated with tenofovir